THE PHARMACOLOGY OF ASPIRIN

阿司匹林的药理学

• 批准号: 7250527
• 负责人: JOHN Alexander OATES
• 金额: $ 46.98万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-20 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250527
• 关键词: acetylation; active sites; aspirin; biomarker; cellular pathology; cyclooxygenase inhibitors; disease /disorder etiology; drug resistance; enzyme activity; gas chromatography mass spectrometry; genetic polymorphism; genotype; human subject; matrix assisted laser desorption ionization; metabolic syndrome; molecular pathology; noninsulin dependent diabetes mellitus; patient oriented research; peroxidation; pharmacogenetics; platelet aggregation; prostaglandin endoperoxide synthase; protein isoforms; thrombosis; thromboxanes; transfection /expression vector; two dimensional gel electrophoresis

Acting as an antiplatelet drug, aspirin substantially reduces the occurrence of myocardial infarction and stroke. Despite its remarkable efficacy, some patients do not respond to the drug, raising the question of whether they are resistant its antiplatelet action. This proposal addresses the interindividual variation in the effect of aspirin. Aspirin inhibits prostaglandin H synthase-1 (PGHS-1) by acetylating Ser530 in the catalytic site, thereby irreversibly inhibiting formation of thromboxane A2, an agonist for platelet aggregation. We present novel evidence that acetylation of the PGH synthases by aspirin is highly regulated by the oxidative state of the enzymes; elevation of peroxide concentration antagonizes acetylation, suggesting that it may require hydrogen bonding of aspirin to Tyr385. As Tyr385 is converted to a radical by PGHS peroxidase activity, we propose to examine the participation of PGHS peroxidase activity in the peroxide-induced reversal of acetylation and to characterize the binding of aspirin in the catalytic site with crystallography to ascertain its position in relation to Tyr385. Extending this finding to patients, we will investigate clinical states, including the metabolic syndrome, that are associated with increased hydroperoxide formation and aspirin resistance. The biomarkers that have been associated with aspirin resistance will be evaluated and new metrics for aspirin's effect on its molecular target examined. High levels of excretion of the thromboxane metabolite, 11 -dehydro-thromboxane B2 (TxM), have been associated with an increased risk of coronary events. We now have evidence that a significant portion of TxM in cigarette smokers derives from an extra-platelet source via the inducible PGHS-2 pathway, implying an inflammatory cell origin. The extent to which extra-platelet PGHS-2 derived TxM contributes to high levels of TxM in patients with coronary disease will be determined and correlated with the PGHS-2 promoter polymorphism, with clinical characteristics, and with inflammatory markers. We have found that the initial inhibition of ADP-induced aggregation by aspirin is lost over weeks of treatment. Proposed studies will determine whether this loss of effect of aspirin is dose-dependent, and will further characterize the changes in platelet function associated with the time-dependent loss of effect, including an analysis of changes in platelet protein expression.

阿司匹林充当抗血小板药物，大大减少了心肌梗塞和中风的发生。 尽管具有显着的功效，但一些患者对这种药物没有反应，提出了他们是否是的问题 抵抗其抗血小板作用。该提议解决了阿司匹林作用的个体差异。阿司匹林 通过催化位点抑制前列腺素H合酶-1（PGHS-1），从而不可逆地 抑制血管烷A2的形成，这是血小板聚集的激动剂。我们提出了新的证据 阿司匹林对PGH合酶的乙酰化受到酶的氧化状态的高度调节。高程 过氧化物浓度拮抗乙酰化，表明它可能需要阿司匹林氢键 Tyr385。由于Tyr385通过PGHS过氧化物酶活性转化为自由基，我们建议检查参与 在过氧化物诱导的乙酰化逆转中PGHS过氧化物酶活性的表征 用晶体学的催化部位的阿司匹林确定其相对于Tyr385的位置。扩展这一发现 对于患者，我们将调查包括代谢综合征在内的临床状态，这些状态与增加有关 氢过氧化物形成和阿司匹林耐药性。与阿司匹林耐药性相关的生物标志物 将评估阿司匹林对其分子靶靶标的影响的新指标。高水平的排泄 血栓烷代谢产物，11-脱氢 - thromboxane B2（TXM），已与增加的风险增加 冠状动脉事件。现在，我们有证据表明，吸烟者中有很大一部分TXM来自 通过诱导的PGHS-2途径通过炎症细胞起源的诱导PGHS-2途径。在多大程度上 冠状动脉疾病患者的PGHS-2派生型PGHS-2导致高水平的TXM会导致 确定并与PGHS-2启动子多态性，具有临床特征以及 炎症标记。我们发现，阿司匹林对ADP诱导的聚集的最初抑制作用丢失了 几周的治疗。拟议的研究将确定阿司匹林的这种影响丧失是否依赖于剂量，并且 将进一步表征与时间有关的效应损失相关的血小板功能的变化，包括 血小板蛋白表达的变化分析。